Vinylglycine (2-aminobut-3-enoic acid)) (Berkowitz et al., Tetrahedron: Asym. (2006) 12: 869) is a natural, non-protein α-amino acid and irreversible inhibitor of enzymes that use pyridoxal phosphate (PLP) as a cofactor, such as a alanine racemase, aspartate aminotransferase, and α-ketoglutarate dehydrogenase (Lacoste et al., (1988) Biochem. Soc. Trans. 16: 606; Rando R. R. (1974) Biochemistry 13: 3859; Lai & Cooper (1986) J. Neurochem. 47: 1376). As a suicide substrate, research has centered on identifying additional natural and synthetic β,γ-olefinic amino acids capable of selectively deactivating enzymes. In addition, protected forms of vinylglycine have been useful in the synthesis of metabotropic glutamate receptors agonists (Selvam et al., (2007) J. Med. Chem. 50: 4656) poly-γ-glutamate synthetase inhibitors (Valiaeva et al., (2001) J. Org. Chem. 66: 5146), and the antitumor antibiotic (+)-FR900482 (Paleo et al., (2003) J. Org. Chem. 68: 130).
Traditionally, the methods of choice to prepare L-vinylglycine have been the pyrolysis of protected methionine sulfoxide (MetO) (Afzali-Ardakani & Rapoport (1980) J. Org. Chem. 45: 4817) and thermolysis of aryl selonoxides obtained from either protected L-glutamate (Hanessian & Sahoo (1984) Tetrahedron Lett. 25: 1425), L-homoserine (Pelliccciari et. al. (1988) Synth. Commun. 69: 7982), or L-homoserine lactone (Berkowitz & Smith (1996) Synthesis 39). For multi-gram syntheses, the MetO pyrolysis approach is most commonly implemented. However, due to the high vacuum (≦3 mm Hg) and temperature (>150° C.) requirements, isomerization is a consistent problem for the reaction.
The migratory occurrence to the more thermally stable β-methyldehydroalanine is further enhanced by the acidity of the α-proton in N,O-protected forms of vinylglycine. The isomer forms quantitatively in the presence of triethylamine or N-methylmorpholine (Afzali-Ardakani & Rapoport (1980) J. Org. Chem. 45: 4817) and it is likewise believed decomposition during silica purification contributes to a optimized yield of 60% (Carrasco et al., (1992) Org. Synth. 70: 29).
Because of the difficulty of isolating the α,β-isomer from protected vinylglycines by chromatography and the desire to find a non-pyrolytic large scale approach, it is desirable for alternative sulfinyl substituents that would syn-eliminate at temperatures below 150° C.